Acanthosis with hyperparakeratosis, the most common mode of abnormal epithelial growth of human oral mucosa, can be consistently induced in the buccal mucosa of rabbits by feeding a zinc-deficient diet. It is postulated that membrane-coating granules play important roles in the homeostasis of epithelial growth and the principal problem in causing acanthosis with hyperparakeratosis is due to impaired exocytosis of these granules. Membrane-coating granules contain hydrolytic enzymes and probably contain growth-inhibition substance. Exocytosis of these granules in the upper spinous cells is suspected to release growth-inhibition substance that is capable of inhibition of cell proliferation. Exocytosis of these granules is also considered to liberate hydrolytic enzymes into the intercellular spaces. The hydrolytic enzymes will disintegrate desmosomes so that surface epithelial cells can desquamate. Failure in exocytosis of membrane-coating granules will result in loss of growth inhibition on one hand and retarded desquamation on the other. The dual effects will therefore cause thickening of the epithelium (acanthosis) and accumulation of parakeratinized cells on the epithelial surface (hyperparakeratosis). The present proposal is designed to prove this hypothesis. Transit times in various phases of the cell cycle will be analyzed and it is expected that in the acanthotic and hyperparakeratotic epithelium of the zinc-deficient rabbits, the G1 and G2 transit times will be greatly reduced due to the suspected decreased release of growth-inhibition substance. Cell production is expected to be increased. Whereas desquamation rate is expected to be decreased due to decreased liberation of hydrolytic enzymes. There is some evidence that exocytosis of membrane-coating granules is mediated by the cell membrane-bound enzyme, adenylate cyclase, and this enzyme is coupled with beta-adrenergic receptor. Part of this project will be carried out to prove that in acanthotic and hyperparakeratotic epithelium of the zinc-deficient rabbits, this enzyme is irresponsive to beta-adrenergic stimulation. Results will demonstrate the important roles of membrane-coating granules in the maintenance of the homeostasis of epithelial growth, and failure of their roles in the pathogenesis of acanthosis and hyperparakeratosis.